Received on April 07, 2003.Approved by the Consultive Council and accepted for publication on April 15, 2005.* Work done at Escola de Medicina da Santa Casa de Misericórdia de Vitória - EMESCAM - Vitória (ES), Brasil.

1 Dermatology specialist at Escola de Medicina da Santa Casa de Misericórdia de Vitória (EMESCAM) Dermatology Service - Vitória (ES), Brasil; Specialist at Sociedade Brasileira de Dermatologia

2 Associate Professor at Escola de Medicina da Santa Casa de Misericórdia de Vitória (EMESCAM) Dermatology Service - Vitória (ES), Brasil.3 Full Professor at Escola de Medicina da Santa Casa de Misericórdia de Vitória (EMESCAM) Graduate Studies in Dermatology - Vitória (ES), Brasil.

© 2 0 0 5 b y Anais Brasileiros de Dermatologia

Recessive dystrophic epidermolysis bullosa mitis - Case report*

Epidermólise bolhosa distrófica recessiva mitis - Relato decaso clínico*

Thaiz Gava Rigoni Gürtler1 Lucia Martins Diniz2 João Basilio de Souza Filho3

Abstract: Epidermolysis bullosa are congenital bullous dermatoses that lead to spontaneousor post-traumatic formation of blisters. There are three recognized disease groups, accordingto the second international consensus: simplex, junctional and dystrophic. The genetic defectof the dystrophic forms is due to a mutation in the COL7A1 gene, which is responsible forcodifying collagen VII, the main representative of anchoring fibrils, which participate in theadherence of the “lamina densa” to the dermis. The authors describe a case of a 15 year-oldfemale patient who presented ulcers on her legs, serous blisters and atrophic scars on herarms and body. Dystrophic ungual and dental abnormalities had also been observed since herbirth. Blister histopathological examination was compatible with epidermolysis bullosa,which, in association with clinical data, allowed the classification of recessive distrophic epi-dermolysis bullosa. Keywords: Collagen type VII; Epidermolysis bullosa; Epidermolysis bullosa dystrophica

Resumo: As epidermólises bolhosas são dermatoses bolhosas congênitas que levam à for -mação de bolhas espontaneamente ou após trauma. São reconhecidos três grupos de dadoença, de acordo com o segundo consenso internacional: simples, juncional e distrófica.Nas formas distróficas, o defeito genético deve-se à mutação no gene COL7A1, responsávelpela codificação do colágeno VII, principal constituinte das fibrilas de ancoragem, que par -ticipam na aderência da lâmina densa à derme. Os autores relatam o caso de paciente dosexo feminino, de 15 anos, apresentando ulcerações nas pernas, bolhas serosas e lesõesatrófico-acastanhadas nos braços e tronco. Foram observadas distrofias ungueais e alter -ações dentárias, iniciadas a partir do nascimento. O exame histopatológico da bolha rev -elou quadro compatível com epidermólise bolhosa, que, associado aos dados clínicos, per -mitiram a classificação do caso na forma distrófica recessiva mitis.Palavras-chave: Colágeno tipo VII; Epidermólise bolhosa; Epidermólise bolhosa distrófica

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Case Report5 0 3

INTRODUCTIONEpidermolysis bullosa (EB) forms a group of

hereditary bullous disorders in which blisters formeither spontaneously or they are triggered by trauma,having this denomination been suggested by Köebnerin 1886.1,2

Basal keratinocytes connect to the dermisthrough the basal membrane area (dermoepidermical

junction), as evidenced by SPA (Schiff's periodic acid)under optic microscopy as a fine, homogenous linearregion. Under electron microscopy, two regions areobserved: lamina lucida, which is electron-sparse,below basal keratinocytes, and another, lamina densaor basalis, above the dermal area that binds to the

upper portion of the latter by anchoring fibrils, whichare electron dense filaments.1

Under optical microscopy, EBs present withblisters in the sudepidermal region and, observingthis region under electron microscopy, over 16 subty-pes were observed and gathered in three maingroups.1,3

1. Epidermolysis bullosa simplex - there isan intraepidermal cleavage at the lower portion,owing to cytolytic alterations of basal keratinocyteswith defects in cytokeratines 5 (KRT5 gene) and 14(KRT14 gene).4 Subtypes: Köebner, Weber-Cockaine,Dowling-Meara and Ogna's variant.

2. Epidermolysis bullosa junctionalis - clea-vage occurs at lamina lucida or at the central regionof the basal membrane area, the ceiling being repre-sented by epidermis and the floor by lamina densa. Itis owed to alterations in laminin-5 (LAMA3, LAMB3,LAMC2 genes), integrin-α6β4 (ITGA6 and ITGB4genes) and transmembrane collagen XVII (COL17A1gene), being the same as bullous pemphigoid anti-gen.4 Subtypes: Herlitz, non-Herlitz e benign genera-lized atrophic.

3. Epidermolysis bullosa dystrophica - clea-vage ocurrs at sublamina densa. Epidermis and lami-na lucida represent the ceiling of the blister and der-mis represents the floor. Alteration is exclusively inCOL7A1 gene.4 Subtypes: Cockaine-Touraine, Pasini,Hallopeau- Siemens and the recessive mitis dystro-phic form.5-7

Acquired epidermolysis bullosa is na auto-anti-body-mediated disease, in which these antibodiesdeposit on lamina and sublamina densa, emerge inadulthood, with formation of blisters in areas submit-ted to trauma, which heal with atrophic scars and mil-ium. In this type of EB there is no mutation, however,immunogenetic studies have demonstrated a connec-tion with HLA DR2.

Chart 1 describes in detail clinical differences,inheritance pattern and prognosis of the subtypes ofepidermolysis bullosa.

Hallopeau-Siemens' dystrophic epidermolysisbullosa corresponds to a severe form, usually lethalin childhood. It presents with hands and feet syne-chia, esophageal stenosis, anemia, growth retarda-tion, dysplastic teeth and atrophic scars on the scalp.Mitis subtype is characterized by more discrete alte-rations, which may vary according to genetic inheri-t a n c e .4 - 7

In EB, both dominant and recessive inheritan-ce patterns are found, up to this date with no associa-tion with histocompatibility antigens (HLA).5-7

According to epidemiological data from theUnited States of America, epidermolysis bullosaoccurs in 50 cases out of 1,000,000 born alive, 92% of

them with simple EB, 5% with dystrophic EB, 1% withjunctional EB and 2% non-classified.8 Data fromNorth Ireland have shown that during a period of 23years (1962-1984), 48 cases of EB were identified,with the following distribution: 31 cases of simple EB(65%), one case of junctional EB (2%), 12 cases ofdystrophic EB (25%) and four cases of the acquiredform (8%).9 In Brazil, there are no epidemiologicaldata.

CASE REPORTWhite, female, 15 year-old patient, student and

residing in the rural area of Afonso Cláudio, ES.Sought medical assistance due to the presence ofwell-outlined, extense and confluent exulcerations inthe leg, covered by an exuberant granulation tissue,without exudation or inflammatory signs (Figure 1),some serous blisters and brown atrophic lesions inthe extensor surface of upper limbs, back and abdo-men, denouncing preexisting blisters.

Upon dermatological examination, no epider-mal cysts, white papulloid lesions, milia and palmary-plantar hyperkeratosis were observed. Hair and bodyhair were normal, and nails presented the followingalterations (Figure 2):

l Anonychia in the first and fifth left toes andungueal hypekeratosis in the third left toe;

l Hyponychia of the right toes;l Finger hyponichia.A total prosthesis of the upper dental arcade

was also observed, and had been used since 12 yearsof age, and lower teeth were irregularly implanted,fractured and brown-yellowish colored.

Previous history indicated that the patient hadbeen born with serous blisters on the scalp and fin-gers, due to delivery trauma. Blisters would burst, lea-ving superficial ulcerations and later atrophichyperchromic lesions. Nails were fragile, brownishand easily detached by trauma, teeth erupted nor-mally, yet, developed with darkening, cavities and fra-gility (Figure 3).

No similar cases were observed in the family.After the elaboration of the diagnostic hypothe-

sis of epidermolysis bullosa, biopsies of two leg blis-ters were carried out. Histopathological examinationrevealed a low cleavage area, in the dermoepidermaljunction, along with vascular congestion, diffuseedema and slight perivascular infiltration oflymphocytes and mononuclear cells in the dermis(Figure 4).

All other laboratory tests - complete bloodcount, clotting tests, biochemistry, seric proteins andstool for parasites - were normal.

Initial therapy consisted on systemic steroidtherapy with prednisone 40 mg/day, systemic antibio-

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tic (erythromycin 2 g/day) and bandages with neomy-cin cream on exulcerated lesions for 10 days. Steroidtherapy was maintained up to this period, with a gra-ded dose reduction until complete suspension(Figure 5).

DISCUSSION EB diagnosis relies on history, physical exami-

nation and blister biopsy, which allows differentia-tion, under optic microscopy, from other bulloses,such as phemphigi. Electron microscopy or directimmunofluorescence evidenced blister cleavage level

in the subepidermal region, thus allowing differentialdiagnosis among EB subtypes. 10

As shown in chart 1, clinical distinction amongEB subtypes is also possible. In the case here descri-bed, the patient presents features of the recessivedystrophic form, albeit with more discrete altera-tions: lesions located in areas more often submittedto trauma, such as knees and extremities, hypertro-phic granulation tissue in the ulcerations, dental andnail abnormalities, leading to classification as mitisf o r m .

Due to the patient's financial difficulties, elec-

FIGURE 3: Irregularly implanted, fractured and Brown-yellowishlower teeth, and total prosthesis in upper dental arcade

FIGURE 2: Right toes hyponychia. Anonychia in the first and fifthleft toes and ungueal hypekeratosis in the third left toe

FIGURE 4: Histopathological examination: (HEx40) blister in thedermoepidermal junction, vascular congestion and diffuse dermal

edema

FIGURE 1:Extense,ulceratedand conflu-ent lesionsin the leg,covered bygranulationtissue - pos-terior andanteriorlesions

tron microscopy and immunofluorescence were notperformed, since they are not available in our service.

Other forms of EB were excluded due to clini-cal signs which were present:

Simple EB: there are no scars, neither unguealor dental alterations;

Junctional EB: it is usually fatal, anemia, syne-chiae, growth retardation, disproteinemia, scaringalopecia, palmary-plantar hyperkeratosis also occur;

Dominant dystrophic EB: presence of whitepapulloid lesions, milia, hypertrophic scars and nor-mal teeth;

Hallopeau-Siemens' recessive dystrophicEB: severe form in which the child usually does notreach adulthood. Presents with hands and feet syne-chia with functional inutility, esophageal stenosis,anemia, growth retardation, dysplastic teeth and atro-phic scars on the scalp. Mitis form is characterized bymore discrete alterations.4-7

In dystrophic EB, the degree of genetic defectvaries from a subtle alteration to a complete absenceof type VII collagen. In recessive forms, mutation ofCOL7A1 gene causes an early interruption of codons,thereby resulting in an absence of collagen VII in thetissues. Mutations that do not cause such early inter-ruption produce less severe forms, such as mitis.3

Mitis form is referred to as being of moderateseverity, and is a consequence of a mutation onCOL7A1 gene, due to a replacement of glycine (mostfrequent mutation),5 leading to alterations of type VIIcollagen,3 which is the major component of ancho-ring fibrils. These collagen alterations can be eitherquantitative or qualitative, hence the phenotype vari-ation.5,11

EB annual incidence in the United States ofAmerica is of 50 cases/1,000,000 born alive, 5% ofthem being dystrophic,6 and moderate severity formsare admitted to be undernotified. Among these is themitis form, which is why only few publications aboutit were found in the litearture.5

Steroid therapy is controversial for epidermoly-sis bullosa: Sampaio & Rivitti suggest the systemic useof corticosteroids, hydantoin (which has an inhibi-tory action on collagenase) and vitamin complemen-tation, whereas Marinkovich et al.3 refer that, becausethese are genetic disorders, no drug is capable of cor-recting the molecular defect, which would thus con-traindicate prolonged steroid use, mainly because ofside effects.

Treatment generally consists of local care (ulce-rations, infections, surgical management) and ofother organs (support with mushy diet, laxatives, vita-min E) and screening for Spinocellular Carcinoma(SCC), in the dystrophic forms.12

Recent studies have identified specific proteinsand genetic abnormalities for the majority of EBsubtypes, advances that have been contributing, inmolecular research, for the development of novelgene and protein therapies.12

Ortiz-Urda et al. (2003) have published a studywith intradermal fybroblast injection, expressing typeVII collagen in integer skin of patients with recessivedystrophic EB and observed that these cells locallyrestored the expression of type VII collagen in vivoand normalized clinical aspects of the disease, inclu-ding subepidermal blisters and anchoring fibrildefects.13

The patient was being treated with prednisone40 mg/day with improvement of the cutaneous pic-ture. A graded reduction of the steroid was employeduntil total suspension, and general measures, such astrauma prevention and local antibiotic drugs, wereadopted, resulting in good clinical control.

The patient is currently being followed up,with visits every 6 months, due to the risk of carcino-matous transformation of skin lesions. Incidence ofthese tumors has been increasing as a consequence ofbetter management and increased survival rates ofthese patients.14

Unlike ultra violet radiation-induced SCCs,these develop in extremities, sites of chronic blisterformation, and have been reported as complication ofchronic infection, since the latter, along with tissuerepairing, is responsible for tissue alterations thatallow tumor formation. Moreover, exposure to repe-titive trauma can lead to a rapid uncontrolled epider-mal growth, with consequent differentiation andtransformation of keratinocytes.14 SCCs are well diffe-rentiated, and yet have worse prognosis and high

Recessive dystrophic epidermolysis bullosa mitis... 507

FI G U R E 5 : After 40 days, a great improvement is observed in thecutaneous picture, due to general hygiene care and local protection

An Bras Dermatol. 2005;80(5):503-8.

distróficas. An Bras Dermatol. 2001; 76: 551-60. 11. Betts CM, Posteraro P, Costa AM, Varotti C, Schubert M,

B r u c k n e r-Tuderman L, et al. Pretibial dystrophicepidermolysis bullosa: a recessively inherited COL7A1 }splice site mutation affecting procolagen VII processing. Br J Dermatol. 1999; 141: 833-9.

12. Marinkovich MP, Pai S. Epidermolysis bullosa: new and emerging trends. Am J Clin Dermatol. 2002; 3: 371-80.

13. Ortiz-Urda S, Lin Q, Green CL, Keene DR, Marinkovich MP, Khavari PA. Injection of genetically engineered fibroblasts corrects regenerated human epidermolysis bullosa skin tissue. J Clin Invest. 2003; 111: 251-5.

14. Bosch RJ, Gallardo MA, Ruiz del Portal G, Sanchez P,Arce MF, Herrera E. Squamous cell carcinoma secondaryto recessive dystrophic epidermolysis bullosa: report of eight tumours in four patients. J Eur Acad Dermatol Venereol. 1999; 13: 198-204.

15. Webr F, Bauer JW, Sepp N, Högler W, Salmhofer W,Hintner H, et al. Squamous cell carcinoma in junctionaland dystrophic epidermolysis bullosa. Acta Derm Venereol. 2001; 81: 189-92.

REFERENCES1. Fonseca JCM, Obadia I. Epidermólise bolhosa: Recentes

avanços. An Bras Dermatol. 1990; 66: 171-4.2. Silva F. Epidermólise bolhosa distrófica: Epidermólise

bolhosa de tendência cicatricial com cistos epidérmicos e formações albo-papulóides. An Bras Dermatol. 1941; 16: 5-11.

3. Marinkovich P. Epidermolysis bullosa. [serial on the Internet]. 2001 [cited 2003 Apr 3];11:[about 9p.]. Available from: www. e m e d i c i n e . c o m / D e r m / To p i c 1 2 4 . h t m

4. Almeida Jr HL. Genética Molecular das Epidermólises Bolhosas. An Bras Dermatol. 2002; 77: 519-32.

5. Ryoo YW, Kim BC, Lee KS. Characterization of mutations of the type VII colagen gene (COL7A1) in recessivedystrophic epidermolysis bullosa mitis (M-RDEB) from three Korean patients. J Dermatol Sci. 2001; 26: 125-32.

6. Vaccaro M, Moretti G, Guarneri F, Cannavò S, Magaudda L. "Sporadic" dystrophic epidermolysis bullosa: a new dominant or mitis recessive mutation? Eur J Dermatol. 2000; 10: 436-8.

7. Hashimoto I, Kon A, Tamai K, Uitto J. Diagnostic dilemmaof "sporadic" cases of dystrophic epidermolysis bullosa: a new dominant or mitis recessive mutation? Exp Dermatol. 1999; 8: 140-2.

8. Horn HM, Tidman MJ. The clinical spectrum of dys-trophic epidermolysis bullosa. Br J Dermatol. 2002; 146: 267-74.

9. McKenna KE, Walsh MY, Bingham EA. Epidermolysis bullosa in Northern Ireland. Br J Dermatol.1992; 127: 318-21.

10. Alves AC F, Cymbalista NC, Oliveira ZNP, Machado MCRM, Sotto MN, Prianti MG, et al. Imunomapeamento no diagnóstico das epidermólises bolhosas hereditárias

MAILING ADDRESS:Thaiz Gava Rigoni Gürtler Av. Nossa Senhora dos Navegantes, 451Ed. Petro Tower - conj 809-811Clinica AngioDerm - Enseada do Suá29050-335 - Vitória - Espírito SantoTel.: (27) 2123-1020E-mail: thaizrig@hotmail.com

mortality rate.15 Treatment for such cases is surgical,which reinforces the importance of early dignosis andintervention.14

The authors emphasize referral to a medicalgenetics service, for orientation about inheritancepatterns and probability of transmission to descen-dants.8 q

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